Alzheimer's disease, characterized by cognitive and behavioral deterioration in its latter stages, has emerged as a significant social and financial concern. With a prevalence approaching 5.5% in the population above the age of 60, the cost for care of Alzheimer's disease patients has been estimated to be in excess of $100 billion annually. Although cholinesterase inhibitors are somewhat effective in reducing the symptoms of Alzheimer's disease, particularly when the disease is in its early phases, they are not at all effective in slowing or stopping the progression of the disease.
Neurofibrillary tangles and neuritic plaques are generally found in the brain regions associated with memory and cognition of those afflicted with Alzheimer's disease. These plaques are also found in the brains of individuals with Down's syndrome, Hereditary Cerebral Hemorrhage of the Dutch-Type, and other neurodegenerative disorders. The neuritic plaques are comprised primarily of amyloid β (Aβ) peptide, a neurotoxic and highly aggregatory peptide segment of amyloid precursor protein (APP). Aβ peptide is formed by the proteolytic cleavage of APP by β-secretase (BRACE) followed by at least one subsequent C-terminal cleavage by γ-secretase. As such, inhibition of BRACE is an attractive target for the treatment or prevention of Alzheimer's disease as well as other diseases characterized pathologically by amyloid plaques.
BRACE is a member of the pepsin sub-family of mammalian aspartic protease and, like its substrate APP, is a type I transmembrane protein. BRACE has been disclosed in the literature and is referred to also as “β-site APP-cleaving enzyme”, “membrane aspartic protease of the pepsin family”, “Asp-2”, “β-secretase”, “membrane-bound aspartic protease” and “Memapsin 2” (See: Ghosh, et al., Current Medicinal Chemistry, 9(11), 1135-1144 (2002)). Two isoforms of BRACE have been identified in humans, designated BACE1 and BACE2. It is believed that the BACE1 inhibitory activity is most important to inhibition of amyloid β (Aβ) peptide (Roggo, Current Topics in Medicinal Chemistry, 2, 359-370 (2002)). Currently described BRACE inhibitors are peptidomimetic transition state analogs, typically containing a hydroxyethyl moiety. Although many of these compounds are potent inhibitors of BRACE, their high molecular weights and low membrane permeability make them poor drug candidates. (See: Park and Lee, Journal of the American Chemical Society, 125(52), 16416-16422 (2003)). Additional compounds described as BRACE inhibitors are disclosed in WO 03/040096, WO 04/024081, WO 04/0039034, and WO 04/043916. Additional BRACE inhibitors are necessary to provide treatments for A-β peptide mediated disorders such as Alzheimer's disease. The present invention provides new inhibitors of BRACE.